Our goal is to elucidate some of the presynaptic mechanisms that control synaptic efficacy. By regulating neurotransmitter release, the activity of specific neuronal pathways can be adapted according to prior activity in the pathway and according to other neuronal and hormonal signals. These processes, we believe, are bases for autonomy in the autonomic nervous system and for functions such as learning and memory in the brain. This project will be a study of nicotinic synaptic transmission in the superior cervical sympathetic ganglion. A particularly fascinating control of synaptic efficacy is the hours-long potentiation of nicotinic transmission that follows a brief burst of preganglionic activity. This "long-term potentiation" is due to an augmentation of acetylcholine (ACh) release. Catecholamines and adenosine are stress-related signal molecules that also regulate nicotinic synaptic efficacy, apparently through regulation of ACh release. It is apparent that presynaptic mechanisms are prominent in the control of synaptic efficacy. To determine what those mechanisms are, isolated nerve terminals are needed. Synaptosomes will be isolated from the rat superior cervical ganglion and will be used in a multidisciplinary approach including electrophysiological and neurochemical measures of synaptic efficacy and ACh release in the intact ganglion. The regulation of ACh metabolism and release in the synaptosomes will be compared to that in the ganglion, providing a critical test of synaptosomes as models for the nerve terminals of the intact tissue. Finally, the synaptosomes will be used to determine the roles of second messengers and ion permeability in controlling ACh release. The superior cervical ganglion offers special advantages for electrophysiological and neurochemical approaches in the study of synaptic transmission. Synaptosomes will add another dimension and will be part of a powerful model system. To further increase that power, liposomes will be investigated as a means of "injecting" impermeant biochemical tools into synaptosomes and nerve terminals. It will then be possible to dissect presynaptic metabol c control mechanisms in ways that were previously impossible.